Pyrrolidylethyl carbazole compounds



Patented Nov. 7, 1950 John BfWright, Kalamazoo, Mich., assignor to The Upjohn' Gompany, Kalamazoo, Mich., a

rcorporation of. Michigan No' Drawing. Application January 21, 1949, Serial No. 72,059

. 6 Claims.

' This invention relates to antihistaminics and is more-particularly concerned with (1) 1- [beta- (l-py'rrolidyl) -ethyl] -carbazole compounds having' the formula wherein Z isthe remainderof a radicalselected from the groii'pf' consistingl of (a) the'carbazole radical, and (1))"; hydrocarbazole radicals having up to'and including four double bonds of the carbazole' radical saturated with hydrogen, and 2) acid addition and quaternary ammonium salts thereof. I T

It is an object of the present invention to provide a novel "group of compounds possessing utility astherapeutics for the treatment of allergic manifestations. A further object of the present inventionis to provide therapeuticallyactive antihistamine compounds which are easily synthesized from readily available materials. Another object of the .present invention is to provide novel antihistaminics containing the pyrrolidyl nucleus. The compounds are addition ally ,useful as intermediates in the preparation of more complex organic molecules. Other objects will become apparent hereinafter.

The foregoing and additionalobjects are accomplished by the provision of compounds of the formula: l

wherein Z is the remainder of a radical selected from the group consisting of carbazoleand hydrogenated carbazole radicals, e.g., those mentioned below, and acid addition and quaternary ammonium salts thereof. 'These novel compounds have been found to counteract histamineinduced spasm of smooth muscle tissue, and are therefore useful in the treatment of various allergic manifestations, such as hay'fever, The radicals comprising the and hydrogenated derivatives of the carbazole radical wherein from one to four double bonds of the ca'rbazoleradicalfare saturated with hydro-'- gen.

depending upon the particular N-sodi'um dihydr0-, tetrahydroe, hexahydroorjoctahydrocarbazole derivative employed as starting mate-1 mula. The compounds of the present invention,

then, are, for example? 9 [beta- 1- pyrrolidyl) -ethyl] -l,2-dihydrocarbazole,

9- [beta-(l-pyrrolidyl) -ethyll -1,2,3,4-tetrahydrocarbazole, V

9- [betal-pyrrolidyl) -ethyl] -1,2,3,4,5,6-hexahydrocarbazole,

9- [beta- (1-pyrrolodyl) -ethyl] 1,2,3,4,10,11-hexahydrocarbazole,

hydrocarbazole, 1 9- -[beta-(1-pyrrolidyl) ethyl] octahydrocarbazole, 7

and acid addition and quaternary ammonium; salts thereof, depending upon the; particular N-sodium carbazole compound reacted with the beta-(l-pyrrolidyll-ethyl chloride "in the con- I densation step, as more fully described in the following.

The free base of the present invention may be conveniently prepared by condensing the N sodium salt of the selected carbazole' compound,

e. g., carbazole, 1,2-dihydrocarbazole, 1,2,13,4-v tetrahydrocarbazole, or '1,2-,3,'4,10,1l-hexahydro 'carbazole, with beta-(l-pyrrolidyl)-ethyl chloride in an aromatic hydrocarbon solvent, e; g.,

toluene or Xylene. The sodium salt of the carba zole may be formed according to known procedure, as by heating the selected carbazole with sodamide at about degrees centigrade using xylene as a solvent, or by'heating the selected carba'zole withmetallic' sodium at a temperatureof -200 degrees centrigrade. V The condensation step may be conveniently efiected'by adding the beta-(l-pyrrolidyl)ethy1 chloride or its hy-' drochloride to a suspension of the selected N The double bonds of the carbazoleradical which may be saturated by hydrogen are in the" 1,2,--the 1,2-,3,4, the l,2,3,4,'10,-11, the 1,2 ,3,4,5,6, the1,2,3,4,5,6,7,8, or the 1,2,3,4,5,6,10,11positions,

I sodium carbazole compound and heating the mixture for several hours at reflux temperature. The sodium chloride, formed as a by-product, is separated and washed to remove any adhering condensation product, the product extracted with acid, the acid extract neutralized, the ,free base extracted with-ether, and fractionally distilled. When-the reaction product is solid, the distillation step is omitted and the product purified by crystallization. This procedure represents a pre- 7 ferred method for the preparation of the corn-.1.

pounds of the present invention, but other solvents and reaction conditions for thecondensation of alkyl halogen compounds. with an amino nitrogen which are known to the art may also be used and will be found satisfactory.

The quaternary ammonium salts of the pres'ent invention which are, for some applications, even.

more desirable than the free base as therapeutic agents, may be prepared in any convenient mannerknown in'theart, as by mixing the free base with an-acid in stoichiometric,proportions, either in.th'e presence of an organic solvent in whichthe salt is insoluble so that precipitation occurs upon formation thereof, or by merely admixing solutions of the acid and amine and evaporating to dryness to yieldthesolid salt. Representativev acids-which may; be used are formic, acetic, citric, picric, sulfuric, hydrochloric, hydrobromic,

hydriodic; phosphoric," succinic, salicylic, and

Acid. addition salts may be formed with the nitrogen atom of'the pyrrolidyl group in all others.

of the compounds of the present invention; and quaternaryammonium acid addition products of the nitrogenatom of the hydrocarbazole radical,

if, such is present, may also be formed. Whether forming agent are merely mixed together; heated to complete the reaction, and the salt thereafter isolated. The quaternary ammonium; salts, are,

in some instances, also valuable as surfacetension depressants and wettingv agents. I

The following examplesare given to illustrate thepresent-invention but are inno way'to be construedas Example 1. 9- [.b'ew- (1 -pyrrolidgjl) -ethyZlcarbazole A suspension of sodamide (prepared from' 3.8

grams of sodium) and 25.1 grams ofcarbazole in 150 milliliters of dry xylene was heated, with stirring, for three hours at l30'degrees centigrade, whereafter 20.0 grams of beta-('l-pyrrolidyD- pended claims.

ethyl chloride was added andthe reaction'heated' under reflux, with stirring, for an additional eight hours. Upon cooling; the reaction mixture was filtered free Ofrthe sodium chloride formed during the condensation; the sodium chloride washed with about 200milliliters of hotxylene, and the xylene washings added to the reaction;

mixture. The combined xylene solutions were extracted with dilute hydrochloric acid, the acid extract made basic with sodium hydroxide solu tion, and the light brown precipitate ofcrudez' 9 etbeta-(ly dyl) ethyl] car zole .co1-..

lected. After air-drying, the product weighted 38.4 grams and melted at 80-81 degrees centigrade.

By dissolving the product in boiling commercial hexane in the presence of activated carbon, filtering, and cooling, there was obtainedlight-yellow needles. of 9- [beta- (1-pyrrolidyl)-ethyl] -car- Example 2. 9- [beta- (1 pyrrolidyl) -ethyll 1,2,3,4-tctrahydrocarbdzole When condensed and isolated according to the procedure-of Example 1, there was obtained from 25.6 grams of 1,2,3,4-tetrahydrocarbazole, sodamide (obtained from 3.8 grams of sodium), and 20.0 grams of beta-(l-pyrrolidyl) -ethyl chloride, a product consisting of 37.0 grams of 9-[beta-(1- pyrrolidyl) -ethyl] -1,2,3,4-tetrahydrocarbazole.

The monohydrochloride was prepared by passing. dry. hydrogen chloride into a solution of 9- [beta 1-pyrrolidyl)-- ethyl] -1,2,3,4-tetrahydro.- carbazole in anhydrous ether. chloride, when purified by crystallization from a mixture of ethyl acetate and. ethanol and decolorizing with activated charcoal, was obtained as light-yellow needles meltinglat 232.5-233 degrees centigrade.

Analysis: Calculated H, 8.27; N. 9.19. Found: 70.74, 8;0 1,"9.42.

. xample 3. -9-lbetd-(i pyrrolidyl) ethyll 1,2,3,4=,10,1 l-hexahydrocarbazole When condensed and isolated according to the procedure of Example 1, there was obtained from 7.5 grams of '1,2,3,4,10,'1l hexahydrocarbazole,

sodamide (obtained from 2.2 0 grams of sodium) and 7.37 grams of beta 1pyrrolidyl) -ethyl chlol,2,3,4,10,11-hexahydrocarbazole, distilling at 147 149 degrees Centigrade under a. pressure of 0.45

millimeter of mercury.

The monohydrochloride, obtained by passing Analysis: Calculated for C18H27Cl: 0,7045;

Various modifications maybe made inthe present invention without departing from the spirit or scope thereof, and it is to be understood that I limit myself only as defined in the ap- Ijclaim:

1. A compound selected from the group-Leon sisting of 1) diamines of'the formula: I

whereinv Z--is-;the. remainder of; a radical selected? from the group consistin (a) carbazole; and,

2. An acid addition salt" of a diamine The hydrowherein Z is the remainder of a radical selected (b) hydrocarbazole radicals having up to and infrom the group consisting of (a) carbazole, and eluding four double bonds of the carbazole radi- (b) hydrocarbazole radicals having up to and in-- cal saturated with hydrogen. eluding 'four double bonds of the carbazole radical 4. 9-[beta-(1-pyrro1idy1) -ethy1]-carbazole. saturated with hydrogen. 5 5. Q-[beta-(l pyrrolidyl)-ethy1]-1,2,3,4,10,11-:

3. A diamine of the formula: hexahydrocarbazole.

CHPOHI 6. 9- [beta- (1 pyrrolidyl) -ethyl] -1,2,3,4,10,11-

hexahydrocarbazole monohydrochloride. t JOHN B. WRIGHT. GHQ-C 10 wherein Z is the remainder of a radical selected No references cited from the group consisting of (a) carbazole, and 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) DIAMINES OF THE FORMULA: 